Download Pathchat no 26 Intravenous immunoglobulins

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Edition no. 26
Intravenous immunoglobulins:
Mode of action and Guidelines for use
Dr. MC Ferreira
M.Med.(Haematology), PG Dip (Transfusion Medicine)
Haematologist
1. Mechanism of immuno-modulation
High doses of immunoglobulin have both anti-inflammatory
effects as well as immuno-suppressive effects and possibly
exert their effects through the following mechanisms 1-2 :
1. It inhibits antibody formation probably through
negative feedback and a reduction of B-cells after
infusion of IVIg.
2. It directly binds the auto-antibodies through antiidiotype antibodies. Anti-idiotypical antibodies in
the IVIg preparation may account for the efficacy
of action seen in patients with acquired
Haemophilia A.
Auto-antibody concentrations
may also decrease after administration of IVIg
because of overall increase in catabolism of IgG.
This happens because the Fc receptors on
phagocytes (protection for IgG against catabolism)
are saturated. The more IVIg is given, the higher the
rate of catabolism.
3. It non-specifically blocks the Fc-receptors on
phagocytes and inhibits the uptake of antibodycoated cells from the circulation in the spleen and
liver. Antibody-mediated cellular toxicity is thus
limited. In immune thrombocytopenic purpura (ITP)
this is probably the dominant mechanism of action
with possibly also ligation of Fc-receptor inhibition. A
similar effect is obtained through use of anti-D in Rhpositive patients with ITP where the antibodycoated red cells “block” the phagocytic system in
the spleen. Anti-Fas antibodies in IVIg bind with Fasligands and blocks apoptosis which is central in
certain necrotising conditions. This is probably one
of many undetermined antibodies present in a
“soup” from different donors' plasma.
4. It decreases inflammatory cytokine release or
action through down-regulation of the immune
activation. This has been eloquently shown in
Kawasaki disease where administration of IVIg, with
binding to Fc-receptors on macrophages resulted
in down-regulation of interleukin-1 release.
5. Antibodies have effects on microbes and toxins. It
may bind to antigens on microbes leading to
opsonification and activation of complement
subsequently enabling lysis of bacteria. It can
neutralize certain toxins known to act as
superantigens (which can directly stimulate Tlymphocytes) leading to the release of proinflammatory cytokines which may compound the
inflammatory reaction (e.g. in toxic shock
syndromes).
6. It inhibits complement-mediated tissue injury
through direct activation of complement, relaying
the downstream complement activation pathway
away from target cell membranes. This is probably
part of the mechanism in dermatomyositis.
7. In immune neutropenia it is unclear whether IVIg is
effective because it may induce neutrophils to
enter the bloodstream or whether it is effective and
prolongs neutrophil survival.
Immune modulation is most probably a combination of
different aspects described above. The effect IVIg may
have on complement activation, macrophages or
through “neutralising“ antibody is most likely not enough to
explain the rapid clinical responses seen, but a
combination may be more likely to explain the
effectiveness.
2. Guidelines for the use of IVIg 3
Dosage
2g/kg, the dose interval is undetermined.
Primary immunodeficiency syndromes or partial humoral
immuno-deficiency
Kawasaki syndrome
It is indicated for the replacement of antibodies and
increase of the level of circulating antibodies in a patient
with primary immunodeficiency syndromes or partial
humoral immunodeficiency.
It is indicated to prevent coronary artery aneurysms in
patients with this disease.
Dosage
0.4-0.6g/kg administered every 3-4 weeks
A trough level is drawn before administration; the baseline
level is at least 500mg/dl.
Trough levels may be determined every 3-6 months.
B-cell chronic lymphocytic leukaemia
It is indicated for the prevention of bacterial infection in
patients with hypogammaglobulinaemia, recurrent
bacterial infections or both in this patient group.
Dosage
0.4g/kg administered once monthly
Immune thrombocytopenic purpura
IVIg is indicated to rapidly raise the platelet count, prevent
or control bleeding, or optimize patients with ITP prior to
surgery
Dosage
0.4g/kg/d for 5 days.
Dosage
1-2g/kg as a single dose in conjunction with aspirin.
Haemolytic disease of the newborn
It is indicated in patients who are haemolysing due to the
presence of maternal antibodies. The aim is to prevent or
reduce the need for exchange and / or top-up transfusion in
these neonates.
Dosage
1-2g/kg as a single dose. It may be repeated once if volume
overload is not problematic.
Note
The only indications Polygam 4 (the product available in
South Africa) is registered for, are:
1. R e p l a c e m e n t t h e r a p y i n p r i m a r y a n t i b o d y
immunodeficiency syndromes
2. Adjunctive therapy in the prevention of infections in
secondary antibody deficiency states
0.4mg/kg may be used as a single maintenance dose when
required.
3. Immuno-modulation in:
a. Immune thrombocytopenic purpura
b. Kawasaki disease.
Bone marrow transplantation
References:
It is indicated in patients 20 years of age or older to prevent
sepsis or other infection, interstitial pneumonitis (infectious or
other) and acute graft-vs.-host disease in the first 100 days
after bone marrow transplantation.
1
Stiehm ER. Appropriate Therapeutic use of
Immunoglobulin. Transfusion Medicine Reviews. 1996.
10(3):203-221.
2
Wiles CM, Brown P, Chapel H et al. Intravenous
immunoglobulin in neurological disease: a specialist
Dosage
High-dose therapy is suggested, probably 2g/kg
intermittently.
review. Journal of Neurology, Neurosurgery and
Psychiatry. 2002. 72:440-448.
3
Orange JS, Hossny EM, Weiler CR et al. Use of intravenous
immunoglobulin in human disease: A review of evidence
Reduction of serious bacterial infection in children with HIV
by members of the Primary Immunodeficiency
Committee of the American Academy of Allergy,
(This is a valid indication according to the FDA. It is definitely
not widely practiced in South Africa possibly due to the cost
of the product.)
The use is advocated to limit serious bacterial infectious
episodes, limit hospitalization and increase infection-free
periods.
Asthma and Immunology. Journal of Allergy and Clinical
Immunology. 2006. 117:S525-53.
4
NBI. Polygam. Package insert. 1993.